Levetiracetam, (−)-(S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide, is a drug useful as a protective agent for treating and preventing hypoxic and ischemic type aggressions of the central nervous system. It is the active ingredient of KEPPRA®, tablets and flavored liquid, indicated as adjunctive therapy in the treatment of partial onset seizures in adults and children four years of age and older with epilepsy.
Levetiracetam was first described in U.S. Pat. No. 4,837,223 (UCB Societe Anonyme) where it is stated that it has particular therapeutic properties compared to the known racemic form (non proprietary name etiracetam). The S-enantiomer, for example, has a ten times higher protective activity against hypoxia and a four times higher protective activity against cerebral ischemia than the racemic mixture.
The U.S. Pat. No. 4,837,223 describes a method for the preparation of levetiracetam which comprises reacting (−)-(S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid successively with alkylhaloformate and with ammonia. Said acid intermediate is, in turn, obtained from racemic (±)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid by a classic optical resolution according to known methods. In example 1, ethyl (±)-alpha-ethyl-2-oxo-1-pyrrolidine acetate is hydrolyzed to give the corresponding racemic acid in the presence of sodium hydroxide; said acid is subjected to chemical resolution by reaction with an optically active base, (+)-(R)-(1-phenyl ethyl)-amine, selective crystallization of diastereoisomeric salts thereof and isolation of the desired enantiomeric form; finally, the resultant (−)-(S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid is converted into the corresponding amide via activation of the carboxyl residue with ethyl chloroformate.
Several alternative processes for the preparation of levetiracetam have been disclosed in the art.
GB 1,309,692 (UCB S.A.) describes the preparation of several N-substituted lactams, including, inter alia, 2-(2-oxo-pyrrolidino)-butyramide, i.e. the racemic form of levetiracetam, by converting the corresponding ester, obtained by reacting the appropriate pyrrolidin-2-one with an appropriate alkyl haloalkylcarboxylate, with gaseous ammonia in methanol (example 2) or by converting the corresponding acid chloride, obtained by reacting the corresponding acid with thionyl chloride, with gaseous ammonia (example 3).
WO 01/64637 (UCB Farchim) describes the preparation of levetiracetam by asymmetric hydrogenation in the presence of a chiral catalyst of (Z) or (E)-2-(2-oxotetrahydro-1H-1-pyrrolyl)-2-butenamide, which in turn is obtained by reacting the corresponding acid with PCl5 to give the corresponding acid chloride, and then with gaseous ammonia.
WO 03/014080 (UCB S.A.) describes a process for the preparation of levetiracetam and analogues thereof comprising the synthesis of the corresponding ester derivative, methyl-(S)-alpha-ethyl-2-oxo-1-pyrrolidine-acetate, and the subsequent ammonolysis reaction in the presence of water.
EP 1,566,376 (REDDYS LAB LTD DR) discloses a process for the preparation of levetiracetam by reacting 4-chlorobutyl chloride with (S)-2-Aminobutyramide hydrochloride, this latter being obtained by first reacting (5)-2-aminobutyric acid hydrochloride with thionyl chloride in methanol to give the corresponding ester hydrochloride, and then reacting the corresponding ester with ammonia in isopropanol.
Several other patents and patent applications describe other approaches to the synthesis of levetiracetam, such as, for example, U.S. Pat. Nos. 6,107,492 and 6,124,473 which describe the preparation of levetiracetam by optical resolution of etiracetam by means of preparative high performance liquid chromatography or continuous simulated moving bed chromatographic system, GB 2,225,322, which describes a process for the preparation of levetiracetam by hydrogenolysis of (S)-alpha-[2-(methylthio)-ethyl]-(2-oxo-1-pyrrolidine)-acetamide in the presence of a desulfurizing agent, and WO 2004/069796, which describes a process for preparing levetiracetam which comprises reacting (S)-2-aminobutyrramide hydrochloride and 4-chlorobutyl chloride in a solvent selected from acetonitrile and methyl tertbutyl ether in the presence of a strong base and recovering the crude product.
Accordingly, notwithstanding the levetiracetam is known since a long time, the efforts of the industry research are still dedicated to find an process for the manufacturing thereof, and there is still the need of an optimized process.